1. Field of the Invention
The present invention relates to a transdermal therapeutic system for the administration of lipophilic, poorly water-soluble and/or sparingly skin-permeable pharmaceutical active substances. More particularly, the present invention relates to a transdermal therapeutic liquid reservoir system for administration of vinpocetine, moxonidine, pergolide or one of their pharmaceutically acceptable salts.
2. Description of the Prior Art
Vinpocetine (ethyl apovincamin-22-oate; 3α16α-apovincaminic acid ethyl ester; ethyl-12-desoxy-12,13-didehydro-vincanol-12-carboxylate) (CAS-No. 42971-09-5) is a pharmaceutical active substance with antioxidant, vasodilating and neuroprotective action which is used for symptomatic treatment of chronic, cerebro-organically caused impairments of performance in the form of impaired memory, impaired concentration, blocking of thought processes, affective disturbances, premature fatigability as well as lack of drive and lack of motivation. At present, this active substance is available on the market only as an oral administration form (tablets) containing 20 mg vinpocetine in the form of its free base—under the brand name CAVINTON®. However, the absorption quota of vinpocetine in a fasting state is only about 6 to 7 percent. Taken during meals, absorption improves by 60 to 100 percent. In both cases, vinpocetine enters the blood stream about half an hour after its administration. With oral administration, its elimination half-life is one to two hours; within eight hours vinpocetine will have been excreted by the body almost completely. In summary, it is to be noted that the bioavailability of orally administered vinpocetine is very poor.
To improve the bioavailability of vinpocetine, a transdermal application with the aid of a transdermal therapeutic system could be taken into consideration. However, the physicochemical properties of vinpocetine are unfavourable for transdermal application. Thus, the partition coefficient log POctanol/Water of about 3.9 and the poor water-solubility of 0.02 μg/ml at room temperature characterise vinpocetine as a very lipophilic pharmaceutical active substance.
Kobayashi, D. et al. (Biol. Pharm. Bull., 16, (1993) 254-258) describe that is possible to achieve a permeation rate of 6.45 μg/cm2×h with an active substance/enhancer mixture, in the form of a 1% suspension of vinpocetine in a mixture of ethanol and 1-menthol, which was applied in-vitro directly to human full-thickness skin. However, this liquid preparation does not enable a continuous release of active substance, but has to be repeatedly applied in order to achieve an almost constant plasma level of vinpocetine over the day. Therefore, such a liquid administration form is likely to meet with little acceptance among patients.